scholarly journals The Pancreatic ß-cell Response to Secretory Demands and Adaption to Stress

Endocrinology ◽  
2021 ◽  
Vol 162 (11) ◽  
Author(s):  
Michael A Kalwat ◽  
Donalyn Scheuner ◽  
Karina Rodrigues-dos-Santos ◽  
Decio L Eizirik ◽  
Melanie H Cobb
Keyword(s):  
Unfolded Protein Response ◽  
Cell Function ◽  
Protein Translation ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Compensatory Mechanisms ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Pancreatic β cells dedicate much of their protein translation capacity to producing insulin to maintain glucose homeostasis. In response to increased secretory demand, β cells can compensate by increasing insulin production capability even in the face of protracted peripheral insulin resistance. The ability to amplify insulin secretion in response to hyperglycemia is a critical facet of β-cell function, and the exact mechanisms by which this occurs have been studied for decades. To adapt to the constant and fast-changing demands for insulin production, β cells use the unfolded protein response of the endoplasmic reticulum. Failure of these compensatory mechanisms contributes to both type 1 and 2 diabetes. Additionally, studies in which β cells are “rested” by reducing endogenous insulin demand have shown promise as a therapeutic strategy that could be applied more broadly. Here, we review recent findings in β cells pertaining to the metabolic amplifying pathway, the unfolded protein response, and potential advances in therapeutics based on β-cell rest.

scholarly journals Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

2016 ◽  
Vol 57 (1) ◽  
pp. R1-R17 ◽  
Author(s):  
Kira Meyerovich ◽  
Fernanda Ortis ◽  
Florent Allagnat ◽  
Alessandra K Cardozo
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Diabetic Patients ◽  
Β Cells ◽  
Β Cell ◽  
Unfolded Protein ◽  
Islet Inflammation ◽  
The Unfolded Protein Response ◽  
Protein Response

Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

scholarly journals The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes

2008 ◽  
Vol 29 (3) ◽  
pp. 317-333 ◽  
Author(s):  
Donalyn Scheuner ◽  
Randal J. Kaufman
Keyword(s):  
Cell Death ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Cell Function ◽  
Mrna Translation ◽  
Β Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degredation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the β-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve β-cell function and/or survival in the treatment of diabetes.

scholarly journals Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

2019 ◽  
Vol 11 (4) ◽  
pp. 375-390 ◽  
Author(s):  
Maikel L. Colli ◽  
Flavia M. Paula ◽  
Lorella Marselli ◽  
Piero Marchetti ◽  
Merja Roivainen ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Unfolded Protein ◽  
Islet Inflammation ◽  
The Unfolded Protein Response ◽  
Protein Response

Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic β cell destruction. The disease is triggered by a combination of genetic and environmental factors, but the mechanisms leading to the triggering of early innate and late adaptive immunity and consequent progressive pancreatic β cell death remain unclear. The insulin-producing β cells are active secretory cells and are thus particularly sensitive to endoplasmic reticulum (ER) stress. ER stress plays an important role in the pathologic pathway leading to autoimmunity, islet inflammation, and β cell death. We show here that group B coxsackievirus (CVB) infection, a putative causative factor for T1D, induces a partial ER stress in rat and human β cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1α branch leads to increased spliced XBP1 expression and c-Jun N-terminal kinase (JNK) activation. Interestingly, JNK1 activation is essential for CVB amplification in both human and rat β cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1α activation. Our findings show that CVB tailors the unfolded protein response in β cells to support their replication, preferentially triggering the pro-viral IRE1α/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway.

scholarly journals Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

2020 ◽  
Author(s):  
René L. Vidal ◽  
Denisse Sepulveda ◽  
Paulina Troncoso-Escudero ◽  
Paula Garcia-Huerta ◽  
Constanza Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Cell Function ◽  
Alpha Synuclein ◽  
Protective Effects ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

scholarly journals Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 19 (21) ◽  
pp. 1902-1917 ◽  
Author(s):  
Guangyu Zhang ◽  
Xiaoding Wang ◽  
Thomas G. Gillette ◽  
Yingfeng Deng ◽  
Zhao V. Wang
Keyword(s):  
Cardiovascular Disease ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Protein Translation ◽  
Ample Evidence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Chronic Disturbance ◽  
The Unfolded Protein Response ◽  
Protein Response

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

Endoplasmic Reticulum Stress Signaling in Disease

2006 ◽  
Vol 86 (4) ◽  
pp. 1133-1149 ◽  
Author(s):  
Stefan J. Marciniak ◽  
David Ron
Keyword(s):  
Diabetes Mellitus ◽  
Endoplasmic Reticulum ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Synthesis ◽  
Unfolded Protein ◽  
Peripheral Insulin Resistance ◽  
Eukaryotic Proteins ◽  
The Unfolded Protein Response ◽  
Protein Response

The extracellular space is an environment hostile to unmodified polypeptides. For this reason, many eukaryotic proteins destined for exposure to this environment through secretion or display at the cell surface require maturation steps within a specialized organelle, the endoplasmic reticulum (ER). A complex homeostatic mechanism, known as the unfolded protein response (UPR), has evolved to link the load of newly synthesized proteins with the capacity of the ER to mature them. It has become apparent that dysfunction of the UPR plays an important role in some human diseases, especially those involving tissues dedicated to extracellular protein synthesis. Diabetes mellitus is an example of such a disease, since the demands for constantly varying levels of insulin synthesis make pancreatic β-cells dependent on efficient UPR signaling. Furthermore, recent discoveries in this field indicate that the importance of the UPR in diabetes is not restricted to the β-cell but is also involved in peripheral insulin resistance. This review addresses aspects of the UPR currently understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.

scholarly journals WFS1 Is a Novel Component of the Unfolded Protein Response and Maintains Homeostasis of the Endoplasmic Reticulum in Pancreatic β-Cells

2005 ◽  
Vol 280 (47) ◽  
pp. 39609-39615 ◽  
Author(s):  
Sonya G. Fonseca ◽  
Mariko Fukuma ◽  
Kathryn L. Lipson ◽  
Linh X. Nguyen ◽  
Jenny R. Allen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals What Is the Sweetest UPR Flavor for the β-cell? That Is the Question

2021 ◽  
Vol 11 ◽  
Author(s):  
Alina Lenghel ◽  
Alina Maria Gheorghita ◽  
Andrei Mircea Vacaru ◽  
Ana-Maria Vacaru
Keyword(s):  
Molecular Mechanisms ◽  
Secretory Cells ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
Specific Outcome ◽  
A Cell ◽  
Protein Response

Unfolded protein response (UPR) is a process conserved from yeasts to mammals and, based on the generally accepted dogma, helps the secretory performance of a cell, by improving its capacity to cope with a burden in the endoplasmic reticulum (ER). The ER of β-cells, “professional secretory cells”, has to manage tremendous amounts of insulin, which elicits a strong pressure on the ER intrinsic folding capacity. Thus, the constant demand for insulin production results in misfolded proinsulin, triggering a physiological upregulation of UPR to restore homeostasis. Most diabetic disorders are characterized by the loss of functional β-cells, and the pathological side of UPR plays an instrumental role. The transition from a homeostatic to a pathological UPR that ultimately leads to insulin-producing β-cell decay entails complex cellular processes and molecular mechanisms which remain poorly described so far. Here, we summarize important processes that are coupled with or driven by UPR in β-cells, such as proliferation, inflammation and dedifferentiation. We conclude that the UPR comes in different “flavors” and each of them is correlated with a specific outcome for the cell, for survival, differentiation, proliferation as well as cell death. All these greatly depend on the way UPR is triggered, however what exactly is the switch that favors the activation of one UPR as opposed to others is largely unknown. Substantial work needs to be done to progress the knowledge in this important emerging field as this will help in the development of novel and more efficient therapies for diabetes.

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